Predicting a treatment response in inflammatory bowel disease

Abstract

In general the present invention concerns a method for predicting the therapeutic outcome of a treatment of in inflammatory bowel disease for anti-TNF agents, anti-α 4 β 7 -integrin agents and/or anti-IL-12/23 agents. The method defines which the agents are likely to provide the best healing effect for a particular patients affected by an inflammatory bowel disease. In particular the method predicts the therapeutic outcome of a treatment of anti-TNF agents in inflammatory bowel disease.

1 .- 21 . (canceled) 
     
     
         22 . A method of determining to which treatment a patient suffering of inflammatory bowel diseases is likely to respond or of determining to which treatment a patient suffering of inflammatory bowel diseases is likely to respond best, the method comprising:
 (i) (a) detecting expression of the genes of a first group consisting of CELSR3, HAAO, FAM135B, F2RL2, CMPK2, SLC28A2, RET, CHP2, PITX1 and GSTT1 in a biological sample from a patient and expression of the genes of a second group consisting of FCER2, CTSL, PTGFRN, GPRC5C, SLAMF7, NR4A2, GNG2, RHOC, SULT1A1, DSC2, NEDD4L, ENGASE, GSN, GNLY, CLEC10A, HLA_DRB5, BAG3, ASGR2, HLA_DRB1 and PTK2 in a biological sample from the patient, and   (b) detecting expression of the genes of a third group consisting of FAM129A, ELM01, TRIP13, PTAR1, ASAH1, SKAP2, HAUS1, C3orf67, SEC14L6, ATP6V0D1, ABCG1, ERAP1, ERV3_1, APOL6 and STON2 in a biological sample from the patient   (c) detecting expression of the TREM1 gene in a biological sample from the patient   (d) comparing the expression level of the genes to a reference expression level,   wherein downregulation of TREM1 expression indicates the future anti-TNF healers or identifies a patient who is likely to respond to treatment with a TNF antagonist,   wherein a different expression level of each of the genes of the first group of genes and of each of the genes of the second group of genes compared to a reference expression level indicates the future anti-IL-12/23 pathway healers or identifies a patient who is likely to respond to treatment with a IL-12/23 pathway antagonist, and   wherein a different expression level of each of the genes the third group of genes compared to a reference expression level indicates the future anti-α 4 β 7 -integrin healers or identifies a patient who is likely to respond to treatment with a α 4 β 7 -integrin antagonist, or   (ii) (a′) detecting expression of the genes of a first group consisting of CELSR3, HAAO, FAM135B, F2RL2, CMPK2, SLC28A2, RET, CHP2, PITX1 and GSTT1 in a biological sample from a patient and expression of the genes of a second group consisting of FCER2, CTSL, PTGFRN, GPRC5C, SLAMF7, NR4A2, GNG2, RHOC, SULT1A1, DSC2, NEDD4L, ENGASE, GSN, GNLY, CLEC10A, HLA_DRB5, BAG3, ASGR2, HLA_DRB1 and PTK2 in a biological sample from the patient, and   (b′) detecting expression of the genes of a third group consisting of PIWIL1, MAATS1, RGS13 and DCHS2 in a biological sample from the patient.   (c′) detecting expression of the TREM1 gene in a biological sample from the patient.   (d′) comparing the expression level of the genes to a reference expression level,   wherein downregulation of TREM1 expression indicates the future anti-TNF healers or identifies a patient who is likely to respond to treatment with a TNF antagonist,   wherein a different expression level each of the genes of the first group of genes and of each of the genes of the second group of genes compared to a reference expression level indicates the future anti-IL-12/23 pathway healers or identifies a patient who is likely to respond to treatment with a IL-12/23 pathway antagonist, and wherein a decreased expression level of each of the genes the third group of genes compared to a reference expression level indicates the future anti-α 4 β 7 -integrin healers or identifies a patient who is likely to respond to treatment with a α 4 β 7 -integrin antagonist.   
     
     
         23 . The method according to  claim 22 , wherein the method comprises:
 (i) (a) detecting expression of the genes of a first group consisting of CELSR3, HAAO, FAM135B, F2RL2, CMPK2, SLC28A2, RET, CHP2, PITX1 and GSTT1 in a colonic tissue sample and expression of the genes of a second group consisting of FCER2, CTSL, PTGFRN, GPRC5C, SLAMF7, NR4A2, GNG2, RHOC, SULT1A1, DSC2, NEDD4L, ENGASE, GSN, GNLY, CLEC10A, HLA_DRB5, BAG3, ASGR2, HLA_DRB1 and PTK2 in a blood sample from the patient; and   (b) detecting expression of the genes of a third group consisting of FAM129A, ELM01, TRIP13, PTAR1, ASAH1, SKAP2, HAUS1, C3orf67, SEC14L6, ATP6V0D1, ABCG1, ERAP1, ERV31, APOL6 and STON2 in a blood sample from the patient   (c) detecting expression of the TREM1 gene in a blood sample from the patient   (d) comparing the expression level of the genes to a reference expression level,   wherein downregulation of TREM1 expression indicates the future anti-TNF healers or identifies a patient who is likely to respond to treatment with a TNF antagonist,   wherein a different expression level each of the genes of the first group of genes and of each of the genes of the second group of genes compared to a reference expression level indicates the future anti-IL-12/23 pathway healers or identifies a patient who is likely to respond to treatment with a IL-12/23 pathway antagonist and   wherein a different expression level of each of the genes the third group of genes compared to a reference expression level indicates the future anti-α 4 β 7 -integrin healers or identifies a patient who is likely to respond to treatment with a α 4 β 7 -integrin antagonist, or   (ii) (a′) detecting expression of the genes of a first group consisting of CELSR3, HAAO, FAM135B, F2RL2, CMPK2, SLC28A2, RET, CHP2, PITX1 and GSTT1 in a colonic tissue sample and expression of the genes of a second group consisting of FCER2, CTSL, PTGFRN, GPRC5C, SLAMF7, NR4A2, GNG2, RHOC, SULT1A1, DSC2, NEDD4L, ENGASE, GSN, GNLY, CLEC10A, HLA_DRB5, BAG3, ASGR2, HLA_DRB1 and PTK2 in a blood sample from the; and   (b′) detecting expression of the genes of a third group consisting of PIWIL1, MAATS1, RGS13 and DCHS2 in sample of colonic tissue sample from the patient   (c′) detecting expression of the TREM1 gene in a blood sample from the patient   (d′) comparing the expression level of the genes to a reference expression level,   wherein downregulation of TREM1 expression indicates the future anti-TNF healers or identifies a patient who is likely to respond to treatment with a TNF antagonist,   wherein a different expression level each of the genes of the first group of genes and of each of the genes of the second group of genes compared to a reference expression level indicates the future anti-IL-12/23 pathway healers or identifies a patient who is likely to respond to treatment with a IL-12/23 pathway antagonist and   wherein a decreased expression level of each of the genes the third group of genes compared to a reference expression level indicates the future anti-α 4 β 7 -integrin healers or identifies a patient who is likely to respond to treatment with a α 4 β 7 -integrin antagonist.   
     
     
         24 . The method according to  claim 22 , wherein the method comprises:
 (a) detecting expression of the genes of a first group consisting of CELSR3, HAAO, FAM135B, F2RL2, CMPK2, SLC28A2, RET, CHP2, PITX1 and GSTT1 in a colonic mucosal biopsy sample and expression of the genes of a second group consisting of FCER2, CTSL, PTGFRN, GPRC5C, SLAMF7, NR4A2, GNG2, RHOC, SULT1A1, DSC2, NEDD4L, ENGASE, GSN, GNLY, CLEC10A, HLA_DRB5, BAG3, ASGR2, HLA_DRB1 and PTK2 in CD14+ monocytes from the patient; and   (b) detecting expression of the genes of a third group consisting of FAM129A, ELM01, TRIP13, PTAR1, ASAH1, SKAP2, HAUS1, C3orf67, SEC14L6, ATP6V0D1, ABCG1, ERAP1, ERV31, APOL6 and STON2 in CD14+ monocytes from the patient   (c) detecting expression of the TREM1 gene in a whole blood cell sample from the patient   (d) comparing the expression level of the genes to a reference expression level, wherein downregulation of TREM1 expression indicates the future anti-TNF healer or identifies a patient who is likely to respond to treatment with a TNF antagonist,   wherein a different expression level of each of the genes the first group of genes and of each of the genes of the second group of genes compared to a reference expression level indicates the future anti-IL-12/23 pathway healers or identifies a patient who is likely to respond to treatment with a IL-12/23 pathway antagonist, and   wherein a different expression level of each of the genes the third group of genes compared to a reference expression level indicates the future anti-α 4 β 7 -integrin healer or identifies a patient who is likely to respond to treatment with a α 4 β 7 -integrin antagonist, or   (ii) (a′) detecting expression of the genes of a first group consisting of CELSR3, HAAO, FAM135B, F2RL2, CMPK2, SLC28A2, RET, CHP2, PITX1 and GSTT1 in a colonic mucosal biopsy sample and expression of the genes of a second group consisting of FCER2, CTSL, PTGFRN, GPRC5C, SLAMF7, NR4A2, GNG2, RHOC, SULT1A1, DSC2, NEDD4L, ENGASE, GSN, GNLY, CLEC10A, HLA_DRB5, BAG3, ASGR2, HLA_DRB1 and PTK2 in CD14+ monocytes from the patient; and   (b′) detecting expression of the genes of a third group consisting of PIWIL1, MAATS1, RGS13 and DCHS2 in a colonic mucosal biopsy sample from the patient   (c′) detecting expression of the TREM1 gene in a whole blood cell sample of the patient.   (d′) comparing the expression level of the genes to a reference expression level,   wherein downregulation of TREM1 expression indicates the future anti-TNF healer or identifies a patient who is likely to respond to treatment with a TNF antagonist,   wherein a different expression level of each of the genes the first group of genes and of each of the genes of the second group of genes compared to a reference expression level indicates the future anti-IL-12/23 pathway healers or identifies a patient who is likely to respond to treatment with a IL-12/23 pathway antagonist and   wherein a decreased expression level of each of the genes the third group of genes compared to a reference expression level indicates the future anti-α 4 β 7 -integrin healers or identifies a patient who is likely to respond to treatment with a α 4 β 7 -integrin antagonist.   
     
     
         25 . The method according to  claim 22 , wherein the expression of the genes or the expression product of the genes in a sample obtained from the patient is a nucleic acid molecule selected from the group consisting of mRNA and cDNA mRNA or polypeptides derived therefrom. 
     
     
         26 . The method according to  claim 22 , wherein the expression of the genes in a sample obtained from the patient is detected by measuring mRNA. 
     
     
         27 . The method according to  claim 22 , wherein the inflammatory bowel disease is ulcerative colitis. 
     
     
         28 . The method according to  claim 22 , wherein the inflammatory bowel disease is Crohn's disease. 
     
     
         29 . The method according to  claim 22 , wherein the patient is a human. 
     
     
         30 . The method according to  claim 22 , wherein the sample analysed for gene expression is obtained from the patient prior to any administration of any of the antagonists to the patient. 
     
     
         31 . The method according to  claim 22 , wherein the sample analysed for gene expression is obtained from the patient after an initial treatment with a selected TNF, α 4 β 7 -integrin or IL-12/23 antagonists to the patient. 
     
     
         32 . The method according to  claim 22 , wherein each sample is from the patient removed sample or biopsy sample and the analysis is in vitro. 
     
     
         33 . The method according to  claim 22 , wherein a TNF antagonist is infliximab or adalimumab. 
     
     
         34 . The method according to  claim 22 , wherein a α 4 β 7 -integrin antagonist is an anti-α 4 β 7 -integrin antibody therapy that blocks action of α 4 β 7 -integrin by preventing Integrin α 4 β 7  forming a complex with the T-cell surface Cd4. 
     
     
         35 . The method according to  claim 22 , wherein a α 4 β 7 -integrin antagonist is an anti-α 4 β 7 -integrin antibody therapy that blocks the action of α 4 β 7 -integrin by preventing α 4 β 7 -integrin of interacting with MadCAM-1. 
     
     
         36 . The method according to  claim 22 , wherein a α 4 β 7 -integrin antagonist is an antibody of the group consisting of a Natalizumab, Vedolizumab, Etrolizumab and AMG-18. 
     
     
         37 . The method according to  claim 22 , wherein an IL-12/23 pathway antagonist is an anti-P40 antibody. 
     
     
         38 . The method according to  claim 22 , wherein an IL-12/23 pathway antagonist is ustekinumab. 
     
     
         39 . The method according to  claim 22 , wherein each sample is a from the patient removed sample or is a biopsy sample and the analysis is in vitro. 
     
     
         40 . A monoclonal anti-TNF antibody or an antigen-binding fragment thereof for use in the treatment of an inflammatory bowel disease, comprising  claim 22  identifying the patient as more likely to respond to a therapy comprising the monoclonal anti-TNF antibody or an antigen-binding fragment thereof and administering the monoclonal anti-TNF antibody or an antigen-binding fragment thereof when the level of mRNA expression measured indicate the patient is a future anti-TNF healer. 
     
     
         41 . A monoclonal anti-α 4 β 7 -integrin antibody or an antigen-binding fragment thereof for use in the treatment of an inflammatory bowel disease, comprising  claim 22  identifying the patient as more likely to respond to a therapy comprising the monoclonal anti-α 4 β 7 -integrin antibody or an antigen-binding fragment thereof and administering the monoclonal anti-α 4 β 7 -integrin antibody or an antigen-binding fragment thereof when the level of mRNA expression measured indicate the patient is a future anti-α 4 β 7 -integrin healer. 
     
     
         42 . A monoclonal directed against IL12 and IL23 or an antibody binds to the p-40 subunit of both IL-12 and IL-23 or the antigen-binding fragment thereof for use in the treatment of an inflammatory bowel disease, comprising  claim 22  identifying the patient as more likely to respond to a therapy comprising the monoclonal antibody or an antigen-binding fragment thereof and administering the monoclonal antibody or an antigen-binding fragment thereof when the level of mRNA expression measured indicate the patient is a future anti-IL-12/23 pathway healer.